This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Approximately 2.5 million people worldwide have been diagnosed with the neurodegenerative disease multiple sclerosis (MS). Though the number of patented drugs continues to rapidly increase, effective treatments for many neural diseases remain elusive because of the complex physiologic pathways involved. Cannabinoids, bioactive compounds from the Cannabis sativa plant, have emerged as promising therapeutic agents for neuroinflammatory conditions found in diseases such as MS. The long-term goal of our work is to characterize these natural compounds as potential therapeutic options for MS and elucidate pathways through which they mediate their effects. In this project's Specific Aim 1 we use cultured glial cells as a model for testing the abilities of cannabinoid compounds[unreadable]ajulemic acid and cannabidiol[unreadable]to suppress markers of neuroinflammation such as nitric oxide and pro-inflammatory cytokines and chemokines. Drugs with such abilities are good candidates for treating diseases characterized by chronic neuroinflammation, such as MS. Since neurodegeneration often results from these inflammatory conditions, an ideal treatment would suppress the inflammatory response and protect surrounding neurons from damage induced by mediators of inflammation. In Specific Aim 2, we test whether our compounds provide such protection. We induce apoptosis in cortical neurons by treatment with 2 toxic inflammatory cytokines, interferon-gamma and tumor necrosis factor-alpha), and assess effectiveness of pre-treatment with our compounds in preventing subsequent neuronal death. In Specific Aim 3, we use cannabinoid receptor antagonists to determine whether observed anti-inflammatory and neuroprotective effects are mediated through classic CB1 and CB2 receptors. Through these proposed aims, we expect to provide the rationale for improved therapeutic options to address chronic neuroinflammation characterizing neurodegenerative diseases like MS. Characterization of the mechanisms by which the cannabinoid compounds mediate disease-modulating effects should aid the development of targeted drugs with less risk and fewer side effects than other classes of pharmaceuticals.